PROJECT SUMMARY/ABSTRACT. There is a fundamental gap in understanding of whether arsenic, a known developmental toxicant, alters maternal immune responses to vaccination and whether exposure to arsenic during pregnancy impairs the transfer of maternal vaccine-induced antibody to the newborn. Moreover, factors known to affect arsenic metabolism and toxicity outcomes, particularly micronutrients critical in one-carbon metabolism, have not been evaluated in studies of arsenic immunotoxicity and vaccine-induced protection in mothers and their newborns. Continued existence of this gap represents an important problem because, until it is filled, optimal points for intervention to prevent arsenic-related immunotoxicity and morbidity during pregnancy and early life will not be known. Our objective is to investigate how maternal arsenic exposure and one-carbon metabolism micronutrient deficiencies alter maternal and newborn influenza antibody titer and avidity, respiratory morbidity, and measures of systemic immune function following maternal influenza vaccination. Our hypothesis is that maternal arsenic exposure and one-carbon metabolism micronutrient deficiencies can alter maternal and newborn influenza antibody titer and avidity, respiratory morbidity, and systemic immune function following influenza vaccination during pregnancy. The rationale for the proposed research is that studying the effects of arsenic exposure on antibody response to vaccination and on immune function could provide insight into mechanisms of human arsenic immunotoxicity and inform new vaccine regimens (higher doses; booster immunizations) to restore protection in arsenic-exposed and malnutrition- affected populations worldwide. Our hypothesis is informed by preliminary findings of associations between maternal arsenic exposure, viral seroconversion, and measures of systemic immune activation in an established pregnancy surveillance system in Bangladesh. Within a cohort of 400 pregnant women and their newborns, we will test our hypothesis by pursuing three specific aims: 1) Establish whether maternal arsenic exposure during pregnancy alters maternal and newborn influenza antibody titer and avidity following maternal influenza vaccination; 2) Determine the association of arsenic exposure with respiratory morbidity in pregnant women and their newborns and whether vaccine-specific and/or systemic immune function mediate this association; and 3) Assess whether arsenic exposure and one-carbon metabolism micronutrient deficiencies during pregnancy have a joint effect on vaccine-specific and/or systemic immune function and respiratory illness in mothers and their newborns. The approach is innovative because it is designed to challenge and shift current research paradigms on the human health consequences of arsenic immunotoxicity. Results from this work will represent a significant advancement in understanding of the extent to which arsenic exposure and one-carbon metabolism micronutrient deficiencies during pregnancy alter maternal and newborn immune response and morbidity following maternal influenza-vaccination.